Lower Glucose Oxidation Research Articles

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

As a result of chronic exposure to high levels of free fatty acids, glucose and inflammatory mediators β-cell apoptosis occurs at the end stage of obesity-associated type 2 diabetes (T2D). One potentially deleterious molecule for β-cell function associated with T2D and obesity in humans is macrophage migration inhibitory factor (MIF). Therefore, the aim of this study was to explore MIF expression in vivo during development of obesity and insulin resistance in high-fat diet (HFD)-fed C57BL/6 mice and whether MIF inhibition could affect β-cell apoptosis and dysfunction induced by palmitic acid (PA) in vitro. Indeed, increase in systemic and locally produced MIF correlated well with the weight gain, triglyceride upregulation, glucose intolerance and insulin resistance, which developed in HFD-fed mice. In in vitro settings PA dose-dependently induced MIF secretion before apoptosis development in islets. Further, mif gene deletion, mRNA silencing or protein inhibition rescued β-cells from PA-induced apoptosis as measured by MTT assay and histone-DNA enzyme linked immuno sorbent assay. Protection from induced apoptosis was mediated by altered activation of caspase pathway and correlated with changes in the level of Bcl-2 family members. Further, MIF inhibition conveyed a significant resistance to PA-induced downregulation of insulin and PDX-1 expression and ATP content. However, β-cell function was not entirely preserved in the absence of MIF judging by low glucose oxidation and depolarized mitochondrial membrane. In conclusion, the observed considerable preservation of β-cells from nutrient-induced apoptosis might implicate MIF as a potential therapeutic target in the later stage of obesity-associated T2D.

Lipid-Induced Insulin Resistance Affects Women Less Than Men and Is Not Accompanied by Inflammation or Impaired Proximal Insulin Signaling

OBJECTIVEWe have previously shown that overnight fasted women have higher insulin-stimulated whole body and leg glucose uptake despite a higher intramyocellular triacylglycerol concentration than men. Women also express higher muscle mRNA levels of proteins related to lipid metabolism than men. We therefore hypothesized that women would be less prone to lipid-induced insulin resistance.RESEARCH DESIGN AND METHODSInsulin sensitivity of whole-body and leg glucose disposal was studied in 16 young well-matched healthy men and women infused with intralipid or saline for 7 h. Muscle biopsies were obtained before and during a euglycemic-hyperinsulinemic clamp (1.42 mU · kg−1 · min−1).RESULTSIntralipid infusion reduced whole-body glucose infusion rate by 26% in women and 38% in men (P < 0.05), and insulin-stimulated leg glucose uptake was reduced significantly less in women (45%) than men (60%) after intralipid infusion. Hepatic glucose production was decreased during the clamp similarly in women and men irrespective of intralipid infusion. Intralipid did not impair insulin or AMPK signaling in muscle and subcutaneous fat, did not cause accumulation of muscle lipid intermediates, and did not impair insulin-stimulated glycogen synthase activity in muscle or increase plasma concentrations of inflammatory cytokines. In vitro glucose transport in giant sarcolemmal vesicles was not decreased by acute exposure to fatty acids. Leg lactate release was increased and respiratory exchange ratio was decreased by intralipid.CONCLUSIONSIntralipid infusion causes less insulin resistance of muscle glucose uptake in women than in men. This insulin resistance is not due to decreased canonical insulin signaling, accumulation of lipid intermediates, inflammation, or direct inhibition of GLUT activity. Rather, a higher leg lactate release and lower glucose oxidation with intralipid infusion may suggest a metabolic feedback regulation of glucose metabolism.

ESPEN Guidelines on Parenteral Nutrition: Geriatrics

Older subjects are at increased risk of partial or complete loss of independence due to acute and/or chronic disease and often of concomitant protein caloric malnutrition. Nutritional care and support should be an indispensable part of their management. Enteral nutrition is always the first choice for nutrition support. However, when patients cannot meet their nutritional requirements adequately via the enteral route, parenteral nutrition (PN) is indicated. PN is a safe and effective therapeutic procedure and age per se is not a reason to exclude patients from this treatment. The use of PN should always be balanced against a realistic chance of improvement in the general condition of the patient. Lower glucose tolerance, electrolyte and micronutrient deficiencies and lower fluid tolerance should be assumed in older patients treated by PN. Parenteral nutrition can be administered either via peripheral or central veins. Subcutaneous administration is also a possible solution for basic hydration of moderately dehydrated subjects. In the terminal, demented or dying patient the use of PN or hydration should only be given in accordance with other palliative treatments.

Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells

High lactate generation and low glucose oxidation, despite normal oxygen conditions, are commonly seen in cancer cells and tumors. Historically known as the Warburg effect, this altered metabolic phenotype has long been correlated with malignant progression and poor clinical outcome. However, the mechanistic relationship between altered glucose metabolism and malignancy remains poorly understood. Here we show that inhibition of pyruvate dehydrogenase complex (PDC) activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. PDC inhibition occurs via enhanced expression of pyruvate dehydrogenase kinase-1 (PDK-1), which results in inhibitory phosphorylation of the pyruvate dehydrogenase alpha (PDHalpha) subunit. We also demonstrate that PDC inhibition in cancer cells is associated with normoxic stabilization of the malignancy-promoting transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) by glycolytic metabolites. Knockdown of PDK-1 via short hairpin RNA lowers PDHalpha phosphorylation, restores PDC activity, reverts the Warburg metabolic phenotype, decreases normoxic HIF-1alpha expression, lowers hypoxic cell survival, decreases invasiveness, and inhibits tumor growth. PDK-1 is an HIF-1-regulated gene, and these data suggest that the buildup of glycolytic metabolites, resulting from high PDK-1 expression, may in turn promote HIF-1 activation, thus sustaining a feed-forward loop for malignant progression. In addition to providing anabolic support for cancer cells, altered fuel metabolism thus supports a malignant phenotype. Correction of metabolic abnormalities offers unique opportunities for cancer treatment and may potentially synergize with other cancer therapies.

Myocardial functional and metabolic parameters in heart failure following chronic high fat feeding

Heart failure (HF) is a complex process that remains to be fully understood, but involves multiple factors. Excess dietary fat is a risk factor for cardiovascular disease, but the role of fatty acids in HF progression has yet to be defined. Lipid accumulation in non-adipose tissue is known to cause a number of pathological events implicating fatty acids in cardiac pathology progression. However, the relationship between dietary lipid and contractile dysfunction is complicated; recent data from human and animal studies suggest dietary fat may be protective following infarction. Previous work in our laboratory using coronary artery ligation demonstrates that rats fed high fat after cardiac injury results in less contractile dysfunction and increased mitochondrial respiration despite increased tissue triglyceride. These results suggest an alteration in substrate utilization that benefits the injured heart. The current study aimed to characterize the impact of high fat on cardiac performance and substrate utilization in rats using a working heart perfusion model. Cardiac output, oxygen consumption (MVO2), and glucose oxidation were measured. Under normal conditions, HF animals had decreased MVO2 with no change in glucose oxidation. However, high fat feeding resulted in increased MVO2 with lower glucose oxidation in sham (SH) and HF animals. Under conditions of increased workload, HF animals had lower cardiac output, MVO2, and glucose oxidation. Furthermore, both SH and HF animals fed high fat had lower cardiac output and glucose oxidation than their respective controls fed normal chow. These results suggest that high dietary fat may not alter cardiac function under normal conditions, but may be deleterious for contractile and metabolic function during increased physiological stress.

Continuous fat oxidation in acetyl–CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity

Acetyl-CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2(-/-) and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulin-stimulated liver and muscle glucose metabolism during a hyperinsulinemic-euglycemic clamp in Acc2(-/-) and WT control mice fed a high-fat diet. Contrary to previous studies that have suggested that increased fat oxidation might result in lower glucose oxidation, both fat and carbohydrate oxidation were simultaneously increased in Acc2(-/-) mice. This increase in both fat and carbohydrate oxidation resulted in an increase in total energy expenditure, reductions in fat and lean body mass and prevention from diet-induced obesity. Furthermore, Acc2(-/-) mice were protected from fat-induced peripheral and hepatic insulin resistance. These improvements in insulin-stimulated glucose metabolism were associated with reduced diacylglycerol content in muscle and liver, decreased PKC activity in muscle and PKCepsilon activity in liver, and increased insulin-stimulated Akt2 activity in these tissues. Taken together with previous work demonstrating that Acc2(-/-) mice have a normal lifespan, these data suggest that Acc2 inhibition is a viable therapeutic option for the treatment of obesity and type 2 diabetes.

Enzyme Electrodes for Glucose Oxidation Prepared by Electropolymerization of Pyrrole

In this work, a method of fabricating enzyme electrodes with the potential application for biofuel cells and biosensors was investigated. Enzyme electrodes were prepared by entrapping native glucose oxidase (GOx) and ferrocene wired GOx (FeFcGOx), as the dopants, in conducting polypyrrole matrices by electropolymerization. Furthermore, the developed polymer enzyme layer was characterized by physical and electrochemical analysis, and glucose oxidation activity on both electrodes was studied. Both electrodes showed direct electrical communication between the enzyme and electrode surface. Low glucose oxidation current was observed from the electrode containing GOx. Higher glucose oxidation current was obtained with FeFcGOx, and the current increased with the escalating glucose concentration suggesting that efficient electron transfer between the enzyme and the electrode surface were achieved. A maximum sensitivity of 20mM for glucose concentration was obtained for the polymer electrode prepared from FeFcGOx.

Retrovirus producer cell line metabolism: implications on viral productivity

The production of retroviral vectors by human cell lines is still hampered by low titers making it relatively difficult to produce very large quantities of this vector of high interest for clinical gene therapy applications. Thus, to improve vector production, we studied the influence of different sugars alone or combinations of sugars on cell growth, vector titers, and metabolism of the producer cell. The use of fructose at 140 mM or a mixed medium (with glucose at 25 mM and fructose at 140 mM) improved the virus titer three- to fourfold, respectively, and the producer cell productivity by fivefold. The increase in the cell productivity was due to a 1.5-fold increase in the vector stability, the remaining increase being due to higher cell specific productivity. The increase in the productivity was associated with lower glucose oxidation and an increase in the lactate and alanine yield. In the mixed medium, an increase in fatty acids derived from the glucose was observed in parallel with a reduction of glutamate and glutamine synthesis via the tricarboxylic acid (TCA) cycle acetyl-CoA and alpha-ketoglutarate, respectively. Although the higher productivities were associated with severe changes in the glycolysis, TCA cycle, and glutaminolysis, the cell energetic status monitored by phosphocreatine and adenosine triphosphate levels was not significantly affected. The synthesis of fatty acids and phospholipids were enhanced in the fructose or mixed media and are possibly key parameters in retroviral vector production.

Effect of age on substrate oxidation during total parenteral nutrition

OBJECTIVE: Parenteral nutrition is increasingly used in the elderly. Aging is accompanied by metabolic changes that can modify substrate use. We compared substrate oxidation during cyclic total parenteral nutrition (TPN) in elderly and middle-aged patients. METHODS: Twelve elderly patients (eight women, four men; 72 ± 5 y) and 12 middle-aged patients (nine women, three men; 39 ± 13 y) who were on cyclic TPN for intestinal failure were investigated while in stable condition after at least 15 d of TPN. No patient was diabetic. Indirect calorimetry was performed during fasting and every 30 min during the 3 h of TPN infusion and 3 h after infusion, allowing the measurement of nutrient oxidation. Blood samples were obtained every hour for the measurement of glucose, insulin, triacylglycerols, and free fatty acids. RESULTS: In the fasting state, resting energy expenditure was significantly higher in the elderly patients than in the middle-aged patients (39.3 ± 8.1 versus 31.9 ± 4.3 kcal/kg of fat-free mass per day, P = 0.008). During TPN, lipid oxidation was significantly higher in the elderly patients than in the middle-aged patients (1.09 ± 0.17 versus 0.84 ± 0.27 mg · kg −1 · min −1, P = 0.011); glucose oxidation was significantly lower in the elderly patients than in the middle-aged patients (2.19 ± 0.93 versus 3.22 ± 1.54 mg · kg −1 · min −1, P = 0.038). Areas under the curves of glycemia and free fatty acids were significantly higher in the elderly patients. CONCLUSION: In the elderly, TPN was associated with significantly higher lipid oxidation and lower glucose oxidation than in younger patients. TPN formulas and flow rates should therefore be adapted in the elderly.

Dichloroacetate improves postischemic function of hypertrophied rat hearts

OBJECTIVESWe sought to determine whether improving coupling between glucose oxidation and glycolysis by stimulating glucose oxidation during reperfusion enhances postischemic recovery of hypertrophied hearts.BACKGROUNDLow rates of glucose oxidation and high glycolytic rates are associated with greater postischemic dysfunction of hypertrophied as compared with nonhypertrophied hearts.METHODSHeart function, glycolysis and glucose oxidation were measured in isolated working control and hypertrophied rat hearts for 30 min before 20 min of global, no-flow ischemia and during 60 min of reperfusion. Selected control and hypertrophied hearts received 1.0 mmol/liter dichloroacetate (DCA), an activator of pyruvate dehydrogenase, at the time of reperfusion to stimulate glucose oxidation.RESULTSIn the absence of DCA, glycolysis was higher and glucose oxidation and recovery of function were lower in hypertrophied hearts than in control hearts during reperfusion. Dichloroacetate stimulated glucose oxidation during reperfusion approximately twofold in both groups, while significantly reducing glycolysis in hypertrophied hearts. It also improved function of both hypertrophied and control hearts. In the presence of DCA, recovery of function of hypertrophied hearts was comparable to or better than that of untreated control hearts.CONCLUSIONSDichloroacetate, given at the time of reperfusion, normalizes postischemic function of hypertrophied rat hearts and improves coupling between glucose oxidation and glycolysis by increasing glucose oxidation and decreasing glycolysis. These findings support the hypothesis that low glucose oxidation rates and high glycolytic rates contribute to the exaggerated postischemic dysfunction of hypertrophied hearts.

4.P.355 Decreased antilipolytic effect of insulin is associated with low glucose oxidation rate and dyslipidemias in familial combined hyperlipidemia

4.P.355 Decreased antilipolytic effect of insulin is associated with low glucose oxidation rate and dyslipidemias in familial combined hyperlipidemia

Metabolic defects in persistent impaired glucose tolerance are related to the family history of non—insulin-dependent diabetes mellitus

Recent studies have suggested that the family history of non—insulin-dependent diabetes mellitus (NIDDM) influences glucose metabolism in subjects with normal glucose tolerance (NGT). However, it is not known whether the family history of NIDDM influences glucose metabolism in impaired glucose tolerance (IGT). We studied in a well-characterized group the impact of family history of NIDDM (diabetes mellitus [DM]-positive) in subjects with IGT on glucose disposal rate (GDR) measured by the euglycemic hyperinsulinemic clamp technique combined with indirect calorimetry. We recruited subjects from our previous population-based studies, and verified their glucose tolerance status twice during the follow-up period of I year. Subjects with NGT (n = 10) and IGT (n = 18) were comparable with respect to age, sex distribution, body mass index, smoking habits, and hypertension. As a group, IGT subjects showed lower GDR than the NGT group (28.6 ± 12.1 v 38.9 ± 13.6 μmol/ kg/ min, P < .05). IGT DM-positive subjects showed a 40% lower GDR than the NGT group ( P < .05) and a 29% lower GDR than IGT DM-negative subjects ( P = NS). IGT DM-positive subjects had lower glucose oxidation ( P = NS, P < .01), glucose nonoxidation ( P = NS, P = .01), and suppression of lipid oxidation ( P = NS, P < .05) during the hyperinsulinemic euglycemic clamp as compared with IGT DM-negative and NGT groups, respectively. In conclusion, in subjects with persistent IGT, the family history of NIDDM is associated with the reduced total whole-body, oxidative, and nonoxidative GDR.

Lipotoxicity in the Pathogenesis of Obesity-Dependent NIDDM: Genetic and Clinical Implications

We review evidence that increased tissue levels of fatty acyl CoA cause the beta-cell abnormalities of nondiabetic obesity and ultimately result in obesity-dependent diabetes. Nondiabetic obesity in Zucker rats is characterized by hypersecretion of insulin at normal fasting and subfasting glucose concentrations. This is a result of beta-cell hyperplasia and increased low Km glucose usage and oxidation. These abnormalities, the hyperinsulinemia, the hyperplasia of beta-cells, i.e., its in vitro equivalent, enhanced bromodeoxyuridine incorporation, and the increased low Km glucose usage can be induced by culturing normal islets with 2 mmol/l free fatty acids (FFAs). Once obese Zucker diabetic fatty rats become diabetic, glucose-stimulated insulin secretion (GSIS) is absent and beta-cell GLUT2 reduced. Islet triglyceride (TG) content is increased 10-fold, probably reflecting increased FFA delivery (plasma FFA levels > 1.5 mmol/l) beginning about 2 weeks before the onset of diabetes. These beta-cell abnormalities, GSIS loss, GLUT2 loss, and TG accumulation, are prevented by reducing plasma FFAs by caloric restriction and by nicotinamide injection. The loss of GSIS and the accumulation of TGs, but not the GLUT2 loss, can be induced in vitro in normal islets cultured in a 2 mmol/l FFA-containing medium, but prediabetic islets seem far more vulnerable to FFA-induced functional impairment and TG accumulation. It is proposed that in uncomplicated obesity, increased lipid availability (FFA levels < 1.5 mmol/l) induces both hyperinsulinemia and insulin resistance in parallel fashion, thereby maintaining normoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of raw potato starch on energy expenditure and substrate oxidation

Because resistant starch (RS) is not absorbed as glucose in the small intestine of healthy humans, postprandial thermogenesis should be lower after the intake of RS as compared with digestible starch. To evaluate this hypothesis, we measured 5-h postprandial thermogenesis and substrate oxidation by indirect calorimetry after ingestion of 50 g pregelatinized (0% RS) and 50 g raw potato starch (54% type II RS) in 15 healthy, normal-weight young males. The subjects consumed each starch (mixed in diluted fruit syrup) twice on separate days and in random order. RS intake was followed by lower thermogenesis (46.5 +/- 13.1 compared with 115.4 +/- 10.4 kJ/5 h; P = 0.008), lower glucose oxidation (P < 0.0005), and greater fat oxidation (P = 0.013) than was pregelatinized starch consumption. Our results suggest that RS has no thermogenic effect and that its presence does not influence the size of the thermic response to digestible starch.

Glycolysis and glucose oxidation during reperfusion of ischemic hearts from diabetic rats

Stimulationg of glucose oxidation by dichloroacetate (DCA) treatment is beneficial during recovery of ischemic hearts from non-diabetic rats. We therfore determined whether DCA treatment of diabetic rat hearts (in which glucose use is extremely low), increases recovery of function of hearts reperfused following ischemia. Isolated working hearts from 6 week streptozotocindiabetic rats were perfused with 11 mM [2- 3H/U- 14C]glucose, 1.2 mM palmitate, 20 μU/ml insulin, and subjected to 30 min of no flow ischemia followed by 60 min reperfusion. Heart function (expressed as the product of heart rate and peak systolic pressure), prior to ischemia, was depressed in diabetic hearts compared to controls (HR × PSP × 10 −3 was 18.2 ± 1 and 24.3 ± 1 beats/mm Hg/min in diabetic and control hearts respectively) but recover to pre-ischemic levels following ischemia, whereas recovery of control of control hearts was significantly decreased (17.8 ± 1 and 11.9 ± 3 beats/mm Hg/min in diabetic and control hearts respectively). This enhanced recovery of diabetic rat hearts occurred even though glucose oxidation during reperfusion was significantly reduced as compared to controls (39 ± 6 and 208 ± 42 nmol/min/g dry wt, in diabetic and control hearts respectively). Glycolytic rate ( 3G 2O production) during reperfusion were similar in diabetic and control hearts (1623 ± 359 and 2071 ± 288 nmol/min/g dry wt, respectively). If DCA (1 mM) was added at reperfusion, hearts from control animals exhibited a significant improvement in function (HR × PSP × 10 − recovered to 20 ± 4 beats/mm Hg/min) that was accompanied by a 4-fold increase in glucose oxidation (from 208 ± 42 to 753 ± 111 nmol/min/g dry wt). DCA was without effect on functional recovery of diabetic rat hearts during reperfusion but did significantly increase glucose oxidation from 39 ± 6 to 179 ± 44 nmol/min/g dry wt). These data suggests that, unlike control hearts, low glucose oxidation rates are not an important factor in reperfusion recovery of previouskly ischemic diabetic rat hearts.

Islet transplantation improves glucose oxidation and mechanical function in diabetic rat hearts.

In poorly controlled diabetes an impairment of glucose use can contribute to a depression in mechanical function of rat hearts. In this study we determined the effects of islet transplantation on glucose use and heart function in streptozotocin-induced diabetic rats. Myocardial function, glycolysis, and glucose oxidation were measured in isolated working hearts obtained from control, diabetic, and islet-transplanted diabetic Wistar-Furth rats. Islets (1200) were transplanted beneath the kidney capsule 2 weeks after a single i.v. dose of streptozotocin (55 mg/kg). The study consisted of three groups: (i) islet-transplanted diabetic rats, (ii) untreated diabetic controls, and (iii) normal controls. Following 11 weeks of monitoring, working hearts were perfused at a 11.5-mmHg (1 mmHg = 133.3 Pa) preload and 80-mmHg afterload, with buffer containing 11 mM [5-3H,14C(U)]glucose, 1.2 mM palmitate, and 100 microU/mL insulin. In untreated diabetic rat hearts, glucose oxidation rates were markedly depressed compared with control hearts (30.4 +/- 4 and 510 +/- 68 nmol.g-1 dry wt..min-1, respectively). Low glucose oxidation rates in diabetic rats were significantly improved in islet-transplanted animals (234 +/- 39 nmol.g-1 dry wt..min-1). The low glucose oxidation rates in untreated diabetic rat hearts were accompanied by an impaired mechanical function compared with control hearts, which was improved by islet transplantation (heart rate x developed pressure x 10(-3) was 10.6 +/- 0.9, 14.8 +/- 1.3, and 14.8 +/- 1.5 beats.mmHg.min-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Altered Maternal Thyroid Function: Fetal and Neonatal Myocardial Metabolism

The influence of the maternal thyroid status on the fetal and neonatal myocardial protein, carbohydrate and lipid metabolism was studied in rats. The neonates born of hypothyroid mothers could not survive beyond 8 days after birth. The offsprings born of hypothyroid mothers showed growth retardation, decreased level of heart mitochondrial protein, reduced myocardial free fatty acid (FFA) oxidation at birth and afterwards, low glucose oxidation by the heart at later fetal stages, and afterwards, despite low heart glycogen reserve, glucose oxidation was high. The offsprings born of hyperthyroid mothers showed stimulation in overall growth, increased myocardial FFA oxidation and increased 14C-glucose incorporation into glycogen as well as increased myocardial glucose oxidation during fetal stages. Results indicate that maternal thyroid hormones play an important role in the metabolic control of fetuses and neonates.

Thermal Environment, Sleep and Energy Metabolism in Piglets

Heat production, respiratory quotient (RQ) and body temperature were measured in 1- to 9-d old piglets during the individual REM sleep episodes and compared with the respective values obtained in non-rapid-eye-movement (NREM) sleep. Two-hour measurements were carried out in· metabolic respiratory chambers under comfortable ther­ mal conditions and upon exposure to cold. Thermal comfort was provided by heating the flocr to 37°C to 38 °C for 1- to 5-d old piglets and to 34°C to 36 °c for the older animals. The air temperature in the chamber ranged between 25°C and 26 0c. Exposure· to cold was produced by decreasing the floor temperature to 28 cc. Under cold exposure the total duration of REM sleep was reduced by 50 to 60 %. Both. the number of REM sleep episodes. and their duration were decreased. Heat production in REM sleep was invariably reduced. Under exposure to cold this decrease was highly significant (P < 0.01) owing to the disappearance of muscular tremor. However, concurrent decrease in body temperature, recorded in 1- to 3-d old piglets, was not significant. In the thermoneutral environment a significant (P < 0.05) decrease in heat production was observed during REM episodes occurring shortly after food intake. By depressing the postprandial thermogenesis, REM sleep contributes apparently to more effective utilization of the food energy. Lower RQ values observed in REM sleep are related to lower glucose oxidation under muscular atony. Sleep, thermal environment, oxygen consumption, RQ

CHRONIC GRANULOMATOUS DISEASE (CGD): ISOLATED DEFECT OF THE NADPH-OXIDASE ACTIVITY IN NEUTROPHILS

CGD is characterized by deficient membrane bound NADPH-oxidase activity in phagocytes. These patients suffer from severe recurrent bacterial and fungal infections. In a boy with typical clinical history of CGD, investigations of his total leukocytes showed reduced cytochemical nitrobluetetrazolium (NBT)-reduction (30-48 % NBT-positive phagocytes), decreased O2−-production in response to the phorbolester PMA and low glucose oxidation. Because in typical CGD-patients at least 99 % of the phagocytes are NBT-negative, we suspected a variant of CGD. Extensive examinations in pure (> 98 %) preparations of polymorphonuclear leukocytes (PMN) gave results compatible with classical CGD: absent production of chemiluminescence and oxygen metabolites (O2−, H2O2) after stimulation with PMA and opsonized zymosan, low glucose oxidation, decreased bactericidal capacity and 99 % NBT-negative PMN. However, in monocytes of the patient, a nearly normal PMA-induced O2−-formation has been found (11.4 nmole O2−/h/2×105 cells, controls 18.2±2.3). The same was true with H2O2-production. In addition the patient's macrophages, cultivated in a long term culture, similarly released oxygen metabolites after stimulation of the respiratory burst with either PMA of opsonized zymosan. We demonstrate here an isolated defect of the NADPH-oxidase activity in neutrophils of a patient with CGD.

Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians.

Previous studies have left unanswered whether human obesity, independent of glucose intolerance, is associated with a "postreceptor" defect in insulin action. We have studied the relationship between the degree of obesity (as estimated by underwater weighing) and the maximal insulin-stimulated glucose disposal rate (M) in vivo in 52 glucose-tolerant Pima Indian males. The relationship was examined independently of differences in age and maximal oxygen uptake (an estimate of "physical fitness"). The maximal insulin-stimulated glucose transport rate (MTR) was also measured in isolated abdominal adipocytes from the same subjects to determine whether differences in M could be explained by differences in glucose transport. The results showed that there was a large variance in M and MTR among these glucose-tolerant subjects. M was better correlated with glucose storage rates than with oxidation rates, as estimated by indirect calorimetry. The most obese subjects had only a 20% lower mean M and 30% lower MTR than the most lean subjects. The lower M in the obese subjects was due to both lower glucose oxidation and storage rates. There was no significant, independent correlation between age or degree of obesity and M or MTR. The maximal oxygen uptake (VO2 max) appeared to independently account for 20% of the variance observed in M. MTR was only weakly correlated with M (r = 0.36, P less than 0.02). We concluded that differences in M in these glucose-tolerant subjects must be explained by factor(s) other than maximal oxygen uptake, age, maximal insulin-stimulated glucose transport in vitro, or degree of adiposity per se.